Randomized, placebo-controlled, double-blind phase I trial of co-administered pyronaridine and piperaquine in healthy adults of sub-Saharan origin.

Drug resistance to sulfadoxine-pyrimethamine and amodiaquine threatens the efficacy of malaria chemoprevention interventions in children and pregnant women. Combining pyronaridine (PYR) and piperaquine (PQP), both components of approved antimalarial therapies, has the potential to protect vulnerable populations from severe malaria. This randomized, double-blind, placebo-controlled (double-dummy), parallel-group, single site phase I study in healthy adult males or females of Black sub-Saharan African ancestry investigated the safety, tolerability, and pharmacokinetics of PYR + PQP (n = 15), PYR + placebo (n = 8), PQP + placebo (n = 8), and double placebo (n = 6) administered orally once daily for 3 days at the registered dose for the treatment of uncomplicated malaria. All participants completed the study. Forty-five adverse events were reported in 26 participants, most (41/45) were mild/moderate in severity, with no serious adverse events, deaths, or study withdrawals. Adverse events were reported in 66.7% (10/15) of participants administered PYR + PQP, 87.5% (7/8) with PYR + placebo, 50.0% (4/8) with PQP + placebo, and 83.3% (5/6) with placebo. For PYR containing regimens, five of 23 participants had asymptomatic transient increases in alanine and/or aspartate aminotransferase. With PQP containing regimens, four of 23 participants had mild Fridericia-corrected QT interval prolongation. Liver enzyme elevations and prolonged QTc interval were consistent with observations for PYR-artesunate and dihydroartemisinin-PQP, respectively, administered to healthy adults and malaria patients. Increases in PYR and PQP exposures were observed following co-administration versus placebo, with substantial interparticipant variability. The findings suggest that PYR + PQP may have potential in chemoprevention strategies. Further studies are needed in the target populations to assess chemoprotective efficacy and define the benefit-risk profile, with special considerations regarding hepatic and cardiac safety.

Efficacy and safety of intravenous ferric carboxymaltose compared with oral iron for the treatment of iron deficiency anaemia in women after childbirth in Tanzania: a parallel-group, open-label, randomised controlled phase 3 trial.

BACKGROUND: Iron deficiency anaemia is of major concern in low-income settings, especially for women of childbearing age. Oral iron substitution efficacy is limited by poor compliance and iron depletion severity. We aimed to assess the efficacy and safety of intravenous ferric carboxymaltose versus oral iron substitution following childbirth in women with iron deficiency anaemia in Tanzania. METHODS: This parallel-group, open-label, randomised controlled phase 3 trial was done at Bagamoyo District Hospital and Mwananyamala Hospital, Tanzania. Eligible participants were close to delivery and had iron deficiency anaemia defined as a haemoglobin concentration of less than 110 g/L and a ferritin concentration of less than 50 µg/L measured within 14 days before childbirth. Participants were randomly assigned 1:1 to receive intravenous ferric carboxymaltose or oral iron, stratified by haemoglobin concentration and site. Intravenous ferric carboxymaltose was administered at a dose determined by the haemoglobin concentration and bodyweight (bodyweight 35 kg to <70 kg and haemoglobin ≥100 g/L: 1000 mg in one dose; bodyweight 35 kg to <70 kg and haemoglobin <100 g/L, or bodyweight ≥70 kg and haemoglobin ≥100 g/L: 1500 mg in two doses at least 7 days apart; bodyweight ≥70 kg and haemoglobin <100 g/L: 2000 mg in two doses at least 7 days apart). Oral iron treatment consisted of three dried ferrous sulphate tablets of 200 mg containing 60 mg of elementary iron and 5 mg of folic acid every morning. Oral treatment was to be taken for 3 months after haemoglobin normalisation. The primary outcome was haemoglobin normalisation (>115 g/L) at 6 weeks. Follow-up visits were at 6 weeks, and 3, 6, and 12 months. Analyses were done in the modified intention-to-treat population of participants who had a 6-week haemoglobin concentration result, using logistic and linear regression models for binary and continuous outcomes, adjusted for baseline haemoglobin concentration and site. This trial is registered with ClinicalTrials.gov, NCT02541708. FINDINGS: Between Oct 8, 2015, and March 14, 2017, 533 individuals were screened and 230 were enrolled and randomly assigned to a study group (114 to intravenous iron, 116 to oral iron). At 6 weeks, 94 (82%) participants in the intravenous iron group and 92 (79%) in the oral iron group were assessed for the primary outcome. 75 (80%) participants in the intravenous iron group and 47 (51%) in the oral iron group had normalised haemoglobin (odds ratio 4·65, 95% CI 2·33-9·27). There were two mild to moderate infusion-related adverse events; and five serious adverse events (three in the intravenous iron group, two in the oral iron group), unrelated to the study medication. INTERPRETATION: Intravenous iron substitution with ferric carboxymaltose was safe and yielded a better haemoglobin response than oral iron. To our knowledge, this is the first study to provide evidence of the benefits and safety of intravenous iron substitution in a low-income setting. FUNDING: Vifor Pharma, R Geigy-Stiftung, Freiwillige Akademische Gesellschaft, and Swiss Tropical and Public Health Institute.

Advice on lifestyle changes (diet, red wine and physical activity) does not affect internal carotid and middle cerebral artery blood flow velocity in patients with carotid arteriosclerosis in a randomized controlled trial.

BACKGROUND: A Mediterranean diet, with and without small daily amounts of red wine, and physical activity reduce the risk of cerebrovascular disease and improve cognition. An increase in cerebral blood flow may be the underlying mechanism. Under normal conditions, cerebral blood flow velocity changes in the internal carotid arteries and in large basal cerebral arteries correlate closely with cerebral blood flow changes, as the diameter of these vessels hardly changes and only the smaller vessels downstream change their diameter. METHODS: A prospective randomized controlled trial was performed in 108 patients with carotid atherosclerosis (mean age 64 years, 67% men, 66% on statin therapy). Half of them were advised to follow a polyphenol-rich modified Mediterranean diet including 1-2 tomatoes, 3-5 walnuts and a bar of dark chocolate (25 g) a day and to perform moderate physical exercise for 30 min/day (lifestyle changes). Within these two groups, half of the patients were randomized either to avoid any alcohol or to drink 100 ml of red wine (women) or 200 ml of red wine (men) daily. Bilateral middle cerebral and internal carotid blood flow velocity (peak systolic, peak end-diastolic and mean) was measured at baseline and after 4 and 20 weeks using colour-coded duplex ultrasound. Insonation depth and insonation angle were used to identically place the sample volume during follow-up investigations. A general linear model with Tukey-Kramer adjustment for multiple comparisons was used to assess the primary end points. For the analysis we used the mean values of the right and left artery. RESULTS: Neither lifestyle changes nor red wine had an effect on peak systolic, peak end-diastolic or mean cerebral blood flow velocity. CONCLUSIONS: Advice on lifestyle changes, including a modified polyphenol-rich Mediterranean diet, a glass of red wine daily and physical exercise, did not affect middle cerebral and internal carotid blood flow velocity in our patient group with carotid atherosclerosis. An increase in cerebral blood flow is thus unlikely to be the cause of the reduced risk of cerebrovascular disease and improved cognitive functioning described in the literature. One possible explanation for the fact that blood flow velocity was not affected by red wine, diet and physical activity advice is that two thirds of our patients were already on statin therapy. Statins increase cerebral blood flow and vasomotor reactivity via nitric oxide.

A daily glass of red wine associated with lifestyle changes independently improves blood lipids in patients with carotid arteriosclerosis: results from a randomized controlled trial.

BACKGROUND: Physical exercise and a Mediterranean diet improve serum lipid profile. The present work studied whether red wine has an effect on top of a lipid-lowering lifestyle in patients with carotid atherosclerosis. METHODS: A prospective randomised unblinded trial was performed from 2009 to 2011 in 108 patients with carotid atherosclerosis, 65% of whom were already on statin therapy with a low mean LDL of 104.9 mg/dl. Half of them were advised to follow a modified Mediterranean diet and to perform moderate physical exercise during 30 min/day (lifestyle changes) for 20 weeks. Within these two groups half of the patients were randomised either to avoid any alcohol or to drink 100 ml of red wine (women) or 200 ml of red wine (men) daily. RESULTS: LDL was significantly lowered by 7% in the lifestyle-changes group compared to the no-lifestyle-changes group (p = 0.0296) after 20 weeks. Lifestyle changes lowered the LDL/HDL ratio after 20 weeks by 8% (p = 0.0242) and red wine independently by 13% (p = 0.0049). The effect on LDL/HDL ratio after 20 weeks was, however, more pronounced in the non-LC group. Total cholesterol (-6%; p = 0.0238) and triglycerides (-13%; p = 0.0361) were lowered significantly by lifestyle changes after 20 weeks compared to the no-lifestyle-changes group. Lipoprotein (a) was not significantly affected by any intervention. The given results are per ITT analysis. CONCLUSIONS: Lifestyle changes including a modified Mediterranean diet and physical exercise as well as a glass of red wine daily improve independently the LDL/HDL ratio in patients with carotid arteriosclerosis even though the vast majority of them was already on statin therapy.

P-glycoprotein modulation by valspodar and cyclosporin does not increase tumor uptake of doxorubicin administered via isolated lung perfusion to rats bearing sarcoma lung metastases.

BACKGROUND: Isolated lung perfusion (ILP) with doxorubicin allows a regional increase in drug exposure while sparing unaffected tissues, but clinical results have so far been disappointing, presumably in part because of the limited tumor penetration of doxorubicin. The aim of this study was to assess whether tumor uptake of doxorubicin, administered locoregionally by ILP, would be increased by the administration of P-glycoprotein (P-gp) modulators. MATERIALS AND METHODS: Single-pass antegrade ILP (A-ILP) was performed with doxorubicin in rats bearing a pulmonary sarcoma nodule which were either untreated or received P-gp inhibitors cyclosporin, valspodar or the vehicle, Cremophor®, only. Doxorubicin concentrations in tumor, lung and effluent were measured by high performance liquid chromatography (HPLC) coupled to spectrofluorimetric detection and the expression of P-gp was examined by Western blot in tumors and lungs. RESULTS: Doxorubicin concentrations in tumors were 5- to 10-fold lower than those measured in lungs tissues. Doxorubicin penetration in tumors, expressed as tumor retention ratios (TR60min), were not different between the groups. Western blot analysis did not show any evidence of baseline or doxorubicin-induced P-gp expression in the tumor model. CONCLUSION: P-gp modulation with cyclosporin or valspodar fails to increase the tumor uptake of doxorubin administered by A-ILP. Other reasons for low doxorubicin penetration in tumor, such as high interstitial fluid pressure or tumor vasculature barrier, or alternate cell membrane drug transporters, need to be examined for a better understanding of impaired doxorubicin delivery to tumor.

A phase I pharmacokinetic study of hypoxic abdominal stop-flow perfusion with gemcitabine in patients with advanced pancreatic cancer and refractory malignant ascites.

PURPOSE: As no curative treatment for advanced pancreatic and biliary cancer with malignant ascites exists, new modalities possibly improving the response to available chemotherapies must be explored. This phase I study assesses the feasibility, tolerability and pharmacokinetics of a regional treatment of gemcitabine administered in escalating doses by the stop-flow approach to patients with advanced abdominal malignancies (adenocarcinoma of the pancreas, n = 8, and cholangiocarcinoma of the liver, n = 1). EXPERIMENTAL DESIGN: Gemcitabine at 500, 750 and 1,125 mg/m(2) was administered to three patients at each dose level by loco-regional chemotherapy, using hypoxic abdominal stop-flow perfusion. This was achieved by an aorto-caval occlusion by balloon catheters connected to an extracorporeal circuit. Gemcitabine and its main metabolite 2',2'-difluorodeoxyuridine (dFdU) concentrations were measured by high performance liquid chromatography with UV detection in the extracorporeal circuit during the 20 min of stop-flow perfusion, and in peripheral plasma for 420 min. Blood gases were monitored during the stop-flow perfusion and hypoxia was considered stringent if two of the following endpoints were met: pH /=1.35. The tolerability of this procedure was also assessed. RESULTS: Stringent hypoxia was achieved in four patients. Very high levels of gemcitabine were rapidly reached in the extracorporeal circuit during the 20 min of stop-flow perfusion, with C (max) levels in the abdominal circuit of 246 (+/-37%), 2,039 (+/-77%) and 4,780 (+/-7.3%) mug/ml for the three dose levels 500, 750 and 1,125 mg/m(2), respectively. These C (max) were between 13 (+/-51%) and 290 (+/-12%) times higher than those measured in the peripheral plasma. Similarly, the abdominal exposure to gemcitabine, calculated as AUC(t0-20), was between 5.5 (+/-43%) and 200 (+/-66%)-fold higher than the systemic exposure. Loco-regional exposure to gemcitabine was statistically higher in presence of stringent hypoxia (P < 0.01 for C (max) and AUC(t0-20), both normalised to the gemcitabine dose). Toxicities were acceptable considering the complexity of the procedure and were mostly hepatic; it was not possible to differentiate the respective contributions of systemic and regional exposures. A significant correlation (P < 0.05) was found between systemic C (max) of gemcitabine and the nadir of both leucocytes and neutrophils. CONCLUSIONS: Regional exposure to gemcitabine-the current standard drug for advanced adenocarcinoma of the pancreas-can be markedly enhanced using an optimised hypoxic stop-flow perfusion technique, with acceptable toxicities up to a dose of 1,125 mg/m(2). However, the activity of gemcitabine under hypoxic conditions is not as firmly established as that of other drugs such as mitomycin C, melphalan or tirapazamine. Further studies of this investigational modality, but with bioreductive drugs, are therefore warranted first to evaluate the tolerance in a phase I study and later on to assess whether it does improve the response to chemotherapy.

Antegrade versus retrograde isolated lung perfusion: doxorubicin uptake and distribution in a sarcoma model.

BACKGROUND: Antegrade and retrograde doxorubicin-based isolated lung perfusions were compared in rodents bearing a sarcomatous tumor in the perfused lung. Inasmuch as these tumors derive their vascularization from the bronchial artery system, we hypothesized that retrograde isolated lung perfusion through the pulmonary vein might result in an improved tumor drug uptake. METHODS: Single-pass antegrade (n = 9) and retrograde (n = 9) isolated left lung perfusions were performed with 100 microg of doxorubicin in Fischer rats 10 days after subpleural tumor cell injection. The perfusion, washout, and recirculation times were 20, 10, and 60 minutes, respectively, followed by harvesting of the lung. The doxorubicin concentration and compartmental distribution in the tumor and in normal parenchyma of each perfused lung were measured by high-pressure liquid chromatography (6 animals of each group) and fluorescence microscopy (3 animals of each group). RESULTS: Doxorubicin concentration and pattern of doxorubicin-based fluorescence signaling were comparable for both perfusion techniques in normal lung tissue. Antegrade and retrograde isolated lung perfusion resulted in similar tumor drug uptake, which was lower than in normal lung parenchyma, and in weak and sporadic fluorescence signaling emerging from the tumor periphery and from blood vessels situated within the tumor tissue. CONCLUSIONS: Retrograde isolated lung perfusion did not confer a better doxorubicin uptake in the tumor as compared with antegrade lung perfusion despite the fact that the tumor vascularization in this model is based on the bronchial artery circulation.

Cytostatic lung perfusion results in heterogeneous spatial regional blood flow and drug distribution: evaluation of different cytostatic lung perfusion techniques in a porcine model.

OBJECTIVES: Comparison of doxorubicin uptake, leakage and spatial regional blood flow, and drug distribution was made for antegrade, retrograde, combined antegrade and retrograde isolated lung perfusion, and pulmonary artery infusion by endovascular inflow occlusion (blood flow occlusion), as opposed to intravenous administration in a porcine model. METHODS: White pigs underwent single-pass lung perfusion with doxorubicin (320 mug/mL), labeled 99mTc-microspheres, and Indian ink. Visual assessment of the ink distribution and perfusion scintigraphy of the perfused lung was performed. 99mTc activity and doxorubicin levels were measured by gamma counting and high-performance liquid chromatography on 15 tissue samples from each perfused lung at predetermined localizations. RESULTS: Overall doxorubicin uptake in the perfused lung was significantly higher (P = .001) and the plasma concentration was significantly lower (P < .0001) after all isolated lung perfusion techniques, compared with intravenous administration, without differences between them. Pulmonary artery infusion (blood flow occlusion) showed an equally high doxorubicin uptake in the perfused lung but a higher systemic leakage than surgical isolated lung perfusion (P < .0001). The geometric coefficients of variation of the doxorubicin lung tissue levels were 175%, 279%, 226%, and 151% for antegrade, retrograde, combined antegrade and retrograde isolated lung perfusion, and pulmonary artery infusion by endovascular inflow occlusion (blood flow occlusion), respectively, compared with 51% for intravenous administration (P = .09). 99mTc activity measurements of the samples paralleled the doxorubicin level measurements, indicating a trend to a more heterogeneous spatial regional blood flow and drug distribution after isolated lung perfusion and blood flow occlusion compared with intravenous administration. CONCLUSIONS: Cytostatic lung perfusion results in a high overall doxorubicin uptake, which is, however, heterogeneously distributed within the perfused lung.